Design and Development of Halogenated Chalcone Derivatives as Potential Anticancer Agents

Uk Jain,R Singh,Ar Rao,Ak Saxena,Rk Bhatia,I Sehar

doi:10.4314/tjpr.v13i1.11

Abstract

Purpose: To design and develop halogenated chalcone derivatives and evaluate them as anticancer agents using different cancer cell lines. Methods: Based on in silico design and docking on known target, crystal structure of the complex of interleukin-1beta converting enzyme (ICE) with a peptide based inhibitor, (3S )-N-Methanesulfonyl-3({1-[N-(2-naphtoyl)-l-valyl]-l-prolyl}amino)-4-oxobutanamide (1BMQ), novel halogenated chalcone derivatives were designed (7a-h) employing LigandFit module of Accelrys (Discovery Studio, 2.1 version). Standard protocols for ligand and protein preparation were employed and their binding orientation validated using (3S)-N-Methanesulfonyl-3-({1-[N-(2-naphtoyl)-l-valyl]-l-prolyl}amino)-4oxobutanamide (MNO 601), a caspase inhibitor as reference standard. Energy minimized conformers with best dock scores were considered for the identification of interacting amino acid residues with ligands. Selected derivatives were synthesized and analyzed by melting point, 1 H NMR, IR and mass spectroscopy. Their evaluation for anticancer activity was carried out using adriamycin, paclitaxel and 5fluorouracil as reference standards on prostrate (PC-3), colon (COLO-205), ovary (OVCAR-5), liver (HEP-2) and neuroblastoma (IMR-32) cancer cell lines, and % growth inhibition and half maximal inhibitory concentration (IC50) values were calculated. Results: Among synthesized compounds, 7b showed the most promising cytotoxic activity with an IC50 of 49.9 µM on colon cancer cell lines (Colo-205), followed by 7d with an IC50 of 66.6 µM against ovarian cancer cell lines (OVCAR-5). Conclusion: We report the successful synthesis, spectral characterization and in vitro anticancer evaluation of a series of novel halogenated chalcone derivatives against a number of human cancer cell lines. The findings indicate the emergence of new anticancer compounds.

Highlights

Chalcones constitute one of the important classes of anticancer agents that have shown promising therapeutic efficacy in the management of human cancers
A series of 4-hydroxy-6-methoxyaurones and 4, 6-dimethoxyaurones, which have binding affinity toward the nucleotide-binding domain of Pglycoprotein, an ABC (ATP-binding cassette) transporter that mediates the resistance of cancer cells to chemotherapy, have been synthesized [7]
The design of the target molecules was based on docking studies with the intention to gain an insight into the binding mode of the most active compounds of the series

Summary

INTRODUCTION

Chalcones constitute one of the important classes of anticancer agents that have shown promising therapeutic efficacy in the management of human cancers. A number of modifications on chalcone chromophore have been reported including hydroxyl [4], methoxy [5], and amino [6] groups as substituents with promising anticancer activity. A series of 4-hydroxy-6-methoxyaurones and 4, 6-dimethoxyaurones, which have binding affinity toward the nucleotide-binding domain of Pglycoprotein, an ABC (ATP-binding cassette) transporter that mediates the resistance of cancer cells to chemotherapy, have been synthesized [7] These compounds differ by the nature of the substituent on the aurone B-ring. They reported a strategy of opening ring B to generate diaryl chalcones and succeeded in getting 2’,4’,6’-trihydroxy-4-iodochalcone (3) with higher affinity with a KD value in nanomolar range [8]. One of them (4) exhibited activity at nanomolar concentrations in vitro [9]

Design of ligands

H H H OCH3 H H OCH3 HHHHHHH

DISCUSSION

CONCLUSION